Viral respiratory infections are major causes of asthma exacerbations. Of the respiratory viruses associated with exacerbations of asthma, RV is the most frequent and possibly most important cause. The goal of this project is to establish the mechanisms by which RV infections exacerbate asthma and to determine why abnormalities in lung function persist long after acute clinical illness. Dr. Busse and his colleagues hypothesize that a major mechanism for asthma exacerbations with colds is RV activation of respiratory epithelium and macrophages that cause the generation of pro-inflammatory cytokines and chemokines. In patients with asthma, this response to RV enhances existing airway inflammation, promotes underlying bronchial hyperresponsiveness and causes wheezing. The applicants also hypothesize that RV activates cytokine/chemokine genes in a wide range of cells as a result of the interaction with RV, or its proteins, that then activate signal transduction mechanisms in the cells. The cytokine/chemokine profile (messenger ribonucleic acid (mRNA) and protein) generated by RV will be determined with in vitro incubation of primary epithelial cells and airway macrophages. The initial focus will be on regulated on activation normal T cell expressed and secreted (RANTES) eotaxin, IL-8, and granulocyte macrophage-colony stimulating factor (GM-CSF). Furthermore, the effect of RV and its individual proteins (i.e., proteases) on bronchial epithelial cells will be established in relationship to activation of cytokine and chemokine genes (RANTES and IL-1-beta), activation of nuclear binding factors (i.e. nuclear factor kappa B (NF kappa B), and their effect on gene transcription and signal transduction. Finally, the in vivo validation of these events will be determined in bronchial epithelial cells obtained from subjects with either natural or experimental infection. From these studies, the applicants will determine the effect of RV on the inflammatory cytokine response of epithelial cells and macrophages and the intracellular mechanisms activated by interaction with RV.